Gilead’s Complera® Non-Inferior to Atripla® Among Treatment-Naïve HIV Patients

-- STaR Study Findings Support Complera as an Important Single Tablet Regimen Option --

GLASGOW, England--(BUSINESS WIRE)--Nov. 15, 2012-- Gilead Sciences (Nasdaq:GILD) today announced Phase 3b clinical trial results from STaR (Single Tablet Regimen), the first head-to-head study comparing the single tablet regimens Complera^® (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) and Atripla^® (efavirenz/emtricitabine/tenofovir disoproxil fumarate) in treatment-naïve adults with HIV infection. Data demonstrated that Complera, which is marketed as Eviplera^® in the European Union, is non-inferior to Atripla based on the proportion of patients with HIV RNA levels (viral load)

Complera demonstrated a statistically significant difference in efficacy compared to Atripla among patients with low baseline viral load (≤ 100,000 copies/mL), and was non-inferior to Atripla among patients with high baseline viral load (> 100,000 copies/mL). Notably, the virologic failure rate was low and comparable between Complera and Atripla, including among patients with baseline viral load up to 500,000 copies/mL. In addition, Complera was well-tolerated with fewer adverse events across all grades and fewer discontinuations due to adverse events (3 percent versus 9 percent; pInternational Congress on Drug Therapy in HIV Infection (HIV11) in Glasgow, United Kingdom.

“Since its U.S. approval in 2006, Atripla has become a standard of HIV care, so the rate of viral suppression demonstrated by Complera in this study is impressive,” said Calvin J. Cohen, MD, M.Sc., Director of Research, Community Research Initiative of New England and principal investigator of the STaR study. “Further, these data reinforce the tolerability profile of Complera and support its role as an important single tablet treatment option for many HIV patients new to therapy.”

At week 48, 86 percent of patients taking Complera (n=338/394) compared to 82 percent of patients taking Atripla (n=320/392) achieved HIV RNA levels U.S. Food and Drug Administration (FDA) snapshot algorithm (95 percent CI for the difference: -1.1 percent to +9.2 percent; predefined criterion for non-inferiority was the lower bound of a two-sided 95 percent CI of -12 percent). Among patients with baseline viral load ≤ 100,000 copies/mL, 89 percent of Complera patients (n=231/260) compared to 82 percent of Atripla patients (n=204/250) achieved viral suppression to 100,000 copies/mL, 80 percent of Complera patients (n=107/134) and 82 percent of Atripla patients (n=116/142) achieved viral suppression to

Virologic failure per snapshot algorithm was defined as patients failing to achieve viral load 100,000 to 500,000 copies/mL; and 25 percent and 16 percent for patients with viral load > 500,000 copies/mL.

Complera was approved in the United States in August 2011 and is indicated for use as a complete regimen for treatment-naïve adults with HIV-1 infection. Complera combines Gilead’s Truvada^® (emtricitabine and tenofovir disoproxil fumarate) with Janssen R&D Ireland’s rilpivirine (marketed as Edurant^®). In previous studies, more rilpivirine-treated patients with viral load > 100,000 copies/mL at the start of therapy experienced virologic failure compared to those with viral load Complera has Boxed Warnings of lactic acidosis/severe hepatomegaly with steatosis and post treatment acute exacerbation of hepatitis B; see below for important safety information.

Complera received marketing authorization from the European Commission as Eviplera in November 2011, becoming the first single tablet regimen approved for patients new to HIV therapy in Europe. In November 2012, Eviplera was added to European AIDS Clinical Society (EACS) treatment guidelines as a recommended regimen for treatment-naïve HIV patients.

About STaR

STaR (Study 110) is an ongoing, randomized (1:1), open-label Phase 3b study evaluating the efficacy and safety of Complera (n=394 treated) compared to Atripla (n=392 treated) among treatment-naïve HIV-positive adults with baseline HIV RNA levels ≥ 2,500 copies/mL. The primary objective of the study is to evaluate the non-inferiority, at a 12 percent margin, of Complera compared to Atripla in achieving HIV RNA levels FDA snapshot algorithm. Secondary endpoints include safety and efficacy of change from baseline in CD4 cell count at weeks 48 and 96 of therapy, and development of genotypic and phenotypic resistance at the time of virologic failure. Randomization was stratified by baseline HIV RNA levels (≤ or > 100,000 copies/mL).

Baseline mean CD4 cell counts were 396 cells/mm³ for Complera patients and 385 cells/mm³ for Atripla patients, and baseline HIV RNA levels were 4.8 log₁₀ copies/mL in both treatment arms. In the Complera and Atripla arms, respectively, at baseline, 66 and 64 percent of patients had HIV RNA levels of ≤ 100,000 copies/mL, 25 percent and 30 percent had HIV-1 RNA levels between 300,000 and 500,000 copies/mL, and 9 percent and 6 percent had HIV-1 RNA levels > than 500,000 copies/mL.

At week 48, changes in CD4 cell counts were +200 cells/mm³ for patients taking Complera and +191 cells/mm³ for patients taking Atripla (p=0.34). The overall virologic failure rate per snapshot algorithm was similar in both treatment arms (8 percent for Complera and 6 percent for Atripla).

Seven percent (n=29) and 14 percent (n=54) of patients in the Complera and Atripla arms, respectively, experienced a Grade 3 or 4 adverse event. The most common treatment-related adverse events occurring in more than 5 percent of Complera patients were headache, insomnia, dizziness, depression, abnormal dreams, anxiety and somnolence.

Laboratory abnormalities (Grade 3-4) occurring in at least one percent of patients in either treatment arm included neutrophils, ALT, AST, GGT, amylase, creatine kinase, hyperglycemia, total cholesterol, glycosuria and hematuria. Only creatine kinase occurred in more than 5 percent of patients (5.1 percent in both arms).

Complera patients experienced lower mean increases compared to Atripla patients in fasting total cholesterol (1 vs. 22 mg/dL) and LDL (1 vs. 14 mg/dL) (p

The mean change in estimated glomerular filtration rate (GFR) by Cockcroft-Gault at week 48 was -5.4 mL/min for the Complera arm and +4.6 mL/min for the Atripla arm (p

Complera Important Product Safety Information and Indication

WARNINGS: LACTIC ACIDOSIS/SEVERE HEPATOMEGALY WITH STEATOSIS and POST TREATMENT ACUTE EXACERBATION OF HEPATITIS B

Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogs, including tenofovir disoproxil fumarate, a component of Complera, in combination with other antiretrovirals.

Complera is not approved for the treatment of chronic hepatitis B virus (HBV) infection and the safety and efficacy of Complera have not been established in patients coinfected with HBV and HIV-1. Severe acute exacerbations of hepatitis B have been reported in patients who are coinfected with HBV and HIV-1 and have discontinued Emtriva or Viread, which are components of Complera. Hepatic function should be monitored closely with both clinical and laboratory follow-up for at least several months in patients who are coinfected with HIV-1 and HBV and discontinue Complera. If appropriate, initiation of anti-hepatitis B therapy may be warranted.

CONTRAINDICATIONS

Complera should not be co-administered with the following drugs, as significant decreases in rilpivirine plasma concentrations may occur due to CYP3A enzyme induction or gastric pH increase, which may result in loss of virologic response and possible resistance to Complera or to the class of NNRTIs:

• the anticonvulsants carbamazepine, oxcarbazepine, phenobarbital, phenytoin
• the antimycobacterials rifabutin, rifampin, rifapentine
• proton pump inhibitors, such as esomeprazole, lansoprazole, omeprazole, pantoprazole, rabeprazole
• the glucocorticoid systemic dexamethasone (more than a single dose)
• St John’s wort (Hypericum perforatum)

WARNINGS AND PRECAUTIONS

• New onset or worsening renal impairmentRenal impairment, including cases of acute renal failure and Fanconi syndrome (renal tubular injury with severe hypophosphatemia), has been reported with the use of tenofovir disoproxil fumarate. Assess creatinine clearance (CrCl) before initiating treatment with Complera. Monitor CrCl and serum phosphorus in patients at risk for renal impairment, including patients who have previously experienced renal events while receiving Hepsera® (adefovir dipivoxil). Avoid administering Complera with concurrent or recent use of nephrotoxic drugs. Patients with CrCl below 50 mL per minute should not receive Complera.

• Drug InteractionsComplera should be used with caution when given with drugs that may reduce the exposure of rilpivirine.Complera should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes.

• Depressive DisordersThe adverse reaction depressive disorders (depressed mood, depression, dysphoria, major depression, mood altered, negative thoughts, suicide attempt, suicidal ideation) has been reported with rilpivirine. During the Phase 3 trials (N = 1,368), the incidence of depressive disorders (regardless of causality, severity) reported among rilpivirine (N = 686) or efavirenz (N = 682) was 8% and 6%, respectively. Most events were mild or moderate in severity. The incidence of Grade 3 and 4 depressive disorders (regardless of causality) was 1% for both rilpivirine and efavirenz. The incidence of discontinuation due to depressive disorders among rilpivirine or efavirenz was 1% in each arm. Suicide attempt was reported in 2 subjects in the rilpivirine arm while suicide ideation was reported in 1 subject in the rilpivirine arm and in 3 subjects in the efavirenz arm. Patients with severe depressive symptoms should seek immediate medical evaluation to assess the possibility that the symptoms are related to Complera, and if so, to determine whether the risks of continued therapy outweigh the benefits.

• Decreases in bone mineral densityBone mineral density (BMD) monitoring should be considered for patients who have a history of pathologic bone fracture or other risk factors for osteoporosis or bone loss. Cases of osteomalacia (associated with proximal renal tubulopathy and which may contribute to fractures) have been reported in association with the use of tenofovir disoproxil fumarate.

• Co-administration with other productsComplera should not be administered concurrently with other medicinal products containing any of the same active components, emtricitabine, rilpivirine, or tenofovir disoproxil fumarate (Emtriva, Edurant, Viread, Truvada, Atripla), with medicinal products containing lamivudine (Epivir, Epivir-HBV, Epzicom, Combivir, Trizivir), or with adefovir dipivoxil (Hepsera).

• Fat redistributionRedistribution/accumulation of body fat has been observed in patients receiving antiretroviral therapy.

• Immune reconstitution syndromeImmune reconstitution syndrome has been reported in patients treated with combination antiretroviral therapy, including the components of Complera. Further evaluation and treatment may be necessary. Autoimmune disorders may occur in the setting of immune reconstitution.

ADVERSE REACTIONS

The most common adverse drug reactions to rilpivirine (incidence greater than or equal to 2%, Grades 2-4) were insomnia and headache.

The most common adverse drug reactions to emtricitabine and tenofovir disoproxil fumarate (incidence ≥ 10%) were diarrhea, nausea, fatigue, headache, dizziness, depression, insomnia, abnormal dreams, and rash.

DRUG INTERACTIONS

• Complera should not be used with drugs where significant decreases in rilpivirine plasma concentrations may occur (See CONTRAINDICATIONS).
• Complera is a complete regimen for the treatment of HIV-1 infection; therefore Complera should not be administered with other antiretroviral medications for the treatment of HIV-1 infection.
• Drugs inducing or inhibiting CYP3A enzymes: Rilpivirine is primarily metabolized by cytochrome P450 (CYP) 3A, and drugs that induce or inhibit CYP3A may thus affect the clearance of rilpivirine. Coadministration of rilpivirine and drugs that induce CYP3A may result in decreased plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs. Coadministration of rilpivirine and drugs that inhibit CYP3A may result in increased plasma concentrations of rilpivirine.
• Drugs increasing gastric PH: Coadministration of rilpivirine with drugs that increase gastric pH may decrease plasma concentrations of rilpivirine and loss of virologic response and possible resistance to rilpivirine or to the class of NNRTIs.
• Drugs affecting renal function: Since emtricitabine and tenofovir are primarily eliminated by the kidneys, coadministration of Complera with drugs that reduce renal function or compete for active tubular secretion may increase serum concentrations of emtricitabine, tenofovir, and/or other renally eliminated drugs. Some examples include, but are not limited to, acyclovir, adefovir dipivoxil, cidofovir, ganciclovir, valacyclovir and valganciclovir.
• QT prolonging drugs: There is limited information available on the potential for a pharmacodynamic interaction between rilpivirine and drugs that prolong the QTc interval of the electrocardiogram. In a study of healthy subjects, supratherapeutic doses of rilpivirine (75 mg once daily and 300 mg once daily) have been shown to prolong the QTc interval of the electrocardiogram. Complera should be used with caution when coadministered with a drug with a known risk of Torsade de Pointes.

DOSAGE AND ADMINISTRATION

Adults: The recommended dose of Complera is one tablet taken orally once daily with a meal.

Renal Impairment: Because Complera is a fixed-dose combination, it should not be prescribed for patients requiring dose adjustment such as those with moderate or severe renal impairment (creatinine clearance below 50 mL per minute).

INDICATION

Complera is indicated for use as a complete regimen for the treatment of HIV-1 infection in antiretroviral treatment-naïve adults. This indication is based on Week 48 safety and efficacy analyses from 2 randomized, double-blind, active controlled, Phase 3 trials in treatment-naïve subjects comparing rilpivirine to efavirenz.

The following points should be considered when initiating therapy with Complera:

• More rilpivirine-treated subjects with HIV-1 RNA greater than 100,000 copies/mL at the start of therapy experienced virologic failure compared to subjects with HIV-1 RNA less than 100,000 copies/mL at the start of therapy
• The observed virologic failure rate in rilpivirine-treated subjects conferred a higher rate of overall treatment resistance and cross-resistance to the NNRTI class compared to efavirenz
• More subjects treated with rilpivirine developed lamivudine/emtricitabine associated resistance compared to efavirenz

Complera is not recommended for patients less than 18 years of age.

About Gilead Sciences

Gilead Sciences is a biopharmaceutical company that discovers, develops and commercializes innovative therapeutics in areas of unmet medical need. The company’s mission is to advance the care of patients suffering from life-threatening diseases worldwide. Headquartered in Foster City, California, Gilead has operations in North America, Europe and Asia Pacific.

Forward-Looking Statement

This press release includes forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995 that are subject to risks, uncertainties and other factors, including the risk that healthcare providers may not recognize the benefits of starting HIV patients new to therapy on Complera. In addition, as Complera is used over longer periods of time by many patients with underlying health problems taking numerous other medicines, Gilead may find new issues such as safety, resistance or drug interaction issues, which may require it to provide additional warnings or contraindications on the label or narrow Complera’s approved indication, each of which could reduce the market acceptance of Complera. These risks, uncertainties and other factors could cause actual results to differ materially from those referred to in the forward-looking statements. The reader is cautioned not to rely on these forward-looking statements. These and other risks are described in detail in Gilead’s Quarterly Report on Form 10-Q for the quarter ended September 30, 2012, as filed with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Gilead, and Gilead assumes no obligation to update any such forward-looking statements.

U.S. full prescribing information for Complera is available at www.Complera.comU.S. full prescribing information for Atripla is available at www.Atripla.comU.S. full prescribing information for Truvada is available at www.Truvada.com

EU Summary of Product Characteristics for Atripla, Eviplera and Truvada are available at www.ema.europa.eu

Complera, Eviplera and Truvada are registered trademarks of Gilead Sciences, Inc.

Atripla is a registered trademark of Bristol-Myers Squibb & Gilead Sciences, LLC.

Edurant is a registered trademark of Janssen R&D Ireland.

For more information on Gilead Sciences, please visit the company’s website at www.gilead.com, follow Gilead on Twitter (@GileadSciences) or call Gilead Public Affairs at 1-800-GILEAD-5 or 1-650-574-3000.

Source: Gilead Sciences, Inc.

Gilead SciencesPatrick O’Brien, Investors, +1 650-522-1936Cara Miller, Media (U.S.), +1 650-522-1616Stephen Head, Media (Europe), +44 (208) 587-2359